Medical use of lasers is a long-standing and well known practice. Uses include photocoagulation (burning or scarification); photodisruption (explosive destruction of tissue); photolysis (cutting or separation of tissue); phototherapy (generation of photochemical effects including ionization and breakage of molecular bonds); photostimulation (inducing molecular aggregation, conformation change, pH change, usually via induced tissue hyperthermia); and photodynamic therapy (laser-induced activation or catalysis of a photosensitive pharmacologic agent). Photocoagulation, photodisruption, photolysis, phototherapy, and photostimulation all describe direct effects of a laser on tissue to achieve a therapeutic effect. These laser-induced therapeutic effects may be employed separately, or in combination with any other therapeutic measure including but not limited to surgery, drug therapy, gene therapy, stem-cell therapy, etc. In photodynamic therapy the laser produces little to no effect of its own and by itself is therapeutically ineffective. Instead, the therapeutic effect of the laser in photodynamic therapy is simply to activate a photo-sensitive drug which is also, by itself, therapeutically ineffective and/or inactive. Thus, the target of the laser in photodynamic therapy is not the tissue or organism, but the drug which has been introduced into the tissue or organism.
With reference now to FIG. 1, a diagrammatic view of an eye, generally referred to by the reference number 10, is shown. When using phototherapy, the laser light is passed through the patient's cornea 12, pupil 14, and lens 16 and directed onto the retina 18. The retina 18 is a thin tissue layer which captures light and transforms it into the electrical signals for the brain. It has many blood vessels, such as those referred to by reference number 20, to nourish it. Various retinal diseases and disorders, and particularly vascular retinal diseases such as diabetic retinopathy, are treated using conventional thermal retinal photocoagulation, as discussed above. The fovea/macula region, referred to by the reference number 22 in FIG. 1, is a portion of the eye used for color vision and fine detail vision. The fovea is at the center of the macula, where the concentration of the cells needed for central vision is the highest. Although it is this area where diseases such as age-related macular degeneration are so damaging, this is the area where conventional photocoagulation phototherapy cannot be used as damaging the cells in the foveal area can significantly damage the patient's vision. Thus, with conventional photocoagulation therapies, the foveal region is avoided.
Photobiology teaches that near-infrared (NIR) lasers have little effect on healthy cells, but tend to restore, by various means, normal function to diseased cells or cells made dysfunctional by pathologic or abnormal environments such as disease. NIR can do this without damaging the cell in any way, instead revitalizing the cell. The inventors proposed this as the mechanism of action of high-density, low-intensity subthreshold diode micropulse laser (SDM), shown to be an effective therapy for retinal diseases, including diabetic retinopathy (see U.S. Publication No. 2013/0317570). In this sense SDM is a clinically harmless form of retinal photostimulation or phototherapy.
Turning to medication therapy, no drug is always effective, and despite initial efficacy, drug tolerance may develop. Due to biologic complexity, safe and effective targeted drug therapy like vascular endothelial growth factor inhibitors (anti-VEGF) medication is difficult and expensive to develop, generally narrow in focus, and often offered late in the disease process due to treatment risks, adverse effects, and expense. Despite application to chronic conditions, drugs are typically short acting. Exemplified by current intravitreal anti-VEGF agents for retinal disease, drug therapy may present extraordinary burdens in terms of clinical access, social resources and economic costs. Thus, despite the great benefits of modern pharmacotherapy, its future as a sustainable global disease management strategy for common and important diseases, including age-related macular degeneration (ARMD) and diabetic retinopathy, appears inevitably limited. Such considerations underscore the need for more widely applicable and accessible treatments. Early and preventive treatments will offer the greatest benefits.
Drug therapy of various disease states is often associated with tachyphylaxis or drug tolerance. In these instances, the target tissue of the drug becomes less or completely unresponsive to the drug effects despite initial effectiveness. Various mechanisms for these processes have been proposed. Drug tolerance is the most common cause of treatment failure in eyes with neurovascular, age-related, macular degeneration (NAMD). The development of drug tolerance may cause failure of treatment medication. Drug tolerance is most often addressed by changing drug dosage (generally increasing); changing drugs; or adding new drugs directed at suppressing the cause of drug unresponsiveness. For instance, in some cases, drug tolerance is thought to be due to an immunologic response to the drug. Thus, additional drugs may be tried to suppress the immune response, permitting the primary drug therapy to become effective once again. However, in many cases none of these options to address unresponsiveness are either available or effective. In such situations treatment is rendered ineffective with subsequent loss of function or life.
A common example of drug tolerance is the treatment of age-related choroidal neovascularization complicating macular degeneration (“wet” ARMD) with various anti-VEGF medications. Pharmacologic inhibitors of VEGF have become the mainstay of treatment for NAMD. They are currently the most effective intervention to reduce macular exudation, choroidal neovascular membrane (CNVM) growth, and most importantly, the risk of visual loss. Thus, ineffectiveness of anti-VEGF medication presents a serious and sight-threatening problem for which there are currently no comparably effective alternatives. Current intravitreal anti-VEGF medications employ pharmacologic (large) doses of medication designed to temporarily remove, by binding, VEGF from the vitreous cavity, retina and submacular space. The main source of VEGF in the retina is the retinal pigment epithelium (RPE). VEGF production is linked to expression of many other factors, the absolute levels and balance of which may be altered with great effect in various disease states, and in response to various treatments, including drugs and retinal laser treatment.
Anti-VEGF injections, typically administered on a near-monthly basis for years, tend to lose effectiveness with repeated use. Use of higher dosages may temporarily improve effectiveness in some cases. The gradual loss of drug effect that may, at times, respond to increased drug dosing—drug tolerance—is generally a permanent condition. This is distinguished from “tachyphylaxis”, in which the loss of drug response tends to develop almost immediately, is not dose-dependent, and may resolve after a period of non-treatment. Thus, “tolerance” appears to best describe the typical loss of response to anti-VEGF treatment of NAMD; and the development of proliferative disease in some eyes despite long-term therapy for diabetic macular edema (DME). Some patients who become unresponsive (tolerant) to one anti-VEGF drug will respond to a different anti-VEGF drug. However, some of these patients eventually become tolerant and unresponsive to all available anti-VEGF medications. Photodynamic therapy with medications such as Verteporfin has been reported to be beneficial as “rescue therapy” in such cases. But, at this point in time, loss of anti-VEGF monotherapy effectiveness generally bodes ill for the visual prognosis.
In the example of “wet” ARMD treatment, one mechanism for the development of tolerance/tachyphylaxis to drugs is “up-regulation”. Typically, drug treatment employs dosages of chemicals that are biologically active but administered in massive quantities compared to the physiologic production of biochemicals normally produced in the body tissues. A common example is VEGF, which is a cytokine (powerful locally acting extracellular protein) produced by various ocular tissues including the neurosensory retina and retinal pigment epithelium. As a normal and innate cytokine, VEGF is associated with both salutary and pathologic effects, depending on the tissue and setting. In “wet” ARMD, VEGF production is pathologically locally elevated by, or causing, the disease process and massive intraocular dosages of anti-VEGF medications are used to bind and/or block VEGF or its action, resulting in a positive therapeutic effect. It has been shown that serial administration of anti-VEGF agents in “wet” ARMD results in progressively less robust therapeutic effectiveness. In some patients, anti-VEGF drugs stop working all together and, absent other effective therapy, loss of vision ensues.
It has been proposed that by repeatedly and chronically extinguishing VEGF produced by retinal tissue, anti-VEGF medications induce the target tissue, by feedback mechanisms, to increase VEGF production. While this “up-regulated” VEGF production may continue to be effectively neutralized by massive and repeated doses of anti-VEGF drug, other clinically harmful effects may occur that are not addressed by the typically narrowly focused inciting drug. For instance, VEGF production is often tied to production of other cytokines which may have similarly potentially clinically harmful effects, such as interleukins (IL) or tissue matrix metalloproteinases (TMMP); and is often associated with decreased production of potentially beneficial cytokines such as Pigment Epithelial Derived Factor (PEDF). It is thought that drug-induced alteration in the cellular expression of these and possibly many other cytokines and other factors known and unknown may be one cause of tolerance/tachyphylaxis observed in the treatment of “wet” ARMD with anti-VEGF drugs. Thus, in this case, initially effective drug therapy has induced a specific state of retinal abnormality eventually rendering the drug ineffective.
Elaboration of cytokines (such as VEGF, IL, TMMP, PEDF, etc) by the retinal pigment epithelium is thought to be a prime driver and determinant of retinal disease. Thus it is reasonable to hypothesize that “normalization of retina function” might include a return toward the cytokine production profiles characteristic of native, normal retina. Thus, in diabetes mellitus, exposure to chronic hyperglycemia and attendant endocrine disturbances may induce chemical changes within the retinal pigment epithelium that lead to altered cytokine expression and a subsequent dysfunction and/or dysregulation of the retina defined as a disease state (diabetic retinopathy).
General laser treatment of the retina for various disorders has been employed for over 50 years. Traditionally, laser photocoagulation characterized by intentional laser-induced thermal destruction and scarification of the retina, has been employed. Due to the clinical effectiveness of retinal laser photocoagulation, the long-held view in medicine was that the beneficial effects of treatment were due to the retinal damage created by photocoagulation. In 2000, one of the named inventors developed a new method of retinal laser treatment (SDM) that did not employ photocoagulative tissue damage or destruction. He demonstrated therapeutically effective treatment of diabetic macular edema (DME) without laser-induced retinal damage or adverse treatment effect detectable by any means presently known. His findings revealed that prior theories of laser mechanism of action for retinal vascular disease, such as diabetic retinopathy, were incorrect as they assumed laser-induced retinal damage as a prerequisite for therapeutic effectiveness. Subsequently, he proposed a new mechanism of retinal laser action based on his observations of SDM. He proposed that SDM worked by “normalizing” retinal function without cellular damage or injury, much as has been shown in prior work in other tissues examined in photobiology. This might occur in many ways including those as yet unknown.
Accordingly, there is a need for a treatment method for the sensitization or re-sensitization of medically unresponsive or diseased tissue. The present invention fulfills these needs and provides other related advantages.